Certain embodiments of the present invention relate to methods and apparatus for assessing the developmental potential of embryos, and in particular to ranking/scoring embryos according to their developmental potential.
Infertility affects more than 80 million people worldwide. It is estimated that 10% of all couples experience primary or secondary infertility. In vitro fertilization (IVF) is an elective medical treatment that may provide a couple who has been otherwise unable to conceive a chance to establish a pregnancy and become parents. It is a process in which eggs (oocytes) are taken from a woman's ovaries and then fertilized with sperm in the laboratory. The embryos created in this process are then placed into the uterus for potential implantation. In between fertilization and transfer the embryos are typically stored in an incubation chamber of an incubator for 2-6 days during which time they may be regularly monitored, for example through imaging, to assess their development. Conditions within the incubator, such as temperature and atmospheric composition, are controlled, generally with a view to emulating the conditions in the oviduct and uterus.
In a typical IVF cycle a number of eggs from a single patient will be fertilized and the resulting embryos incubated. However, it is usual for not all incubated embryos to be transferred to the patient's uterus. This is to reduce the risk of potentially dangerous multiple births. Embryos will typically be selected for transfer on the basis of an assessment of the development potential of the embryos that have been incubated. Embryos determined to have the greatest potential for developing into a live birth will be preferentially selected over other embryos in their cohort. Accordingly, an important aspect of IVF treatment is assessing development potential of the embryos comprising a cohort, i.e. determining embryo quality where embryo quality is a prediction representing the likelihood of an embryo successfully implanting, developing in the uterus after transfer and leading to the birth of a healthy baby.
A powerful tool for assessing embryo quality that has developed over recent years is time-lapse embryo imaging. Time-lapse embryo imaging involves obtaining images of embryos during their development. This can allow the timings of various developmental events, such as cell divisions, and/or the presence or absence of other characteristics relating to the development of an embryo, for example in terms of cell-uniformity (evenness) at different stages, the appearance of pro-nuclei (PN), and the presence of multi-nucleation (MN), to be established.
These timings and characteristics may sometimes be referred to as morphokinetic/morphological parameters for the embryo. In this regard, the terms “morphokinetic” and “morphological” will generally be used herein interchangeably, although in some respects morphokinetic characteristics may strictly be considered a subset of morphological characteristics, namely those morphological characteristics specifically relating to timings. Studies have shown how the timings and durations of various embryonic development events and the presence or absence of various other development characteristics can be correlated with development potential for an embryo.
Models for embryo selection (i.e. models for assessing the developmental potential of an embryo) that take account of morphokinetic parameters can be constructed, evaluated and validated using Known Implantation Data (KID), whereby positive KID embryos are ones which are known to have subsequently implanted and negative KID embryos are ones which are known not to have subsequently implanted.
As an example of a simple model for assessing an embryo's development potential, a relatively early time of division from one cell to two cells has been found to be an indicator of a good quality embryo. Other morphokinetic parameters, for example the degree of synchronicity in the two divisions when dividing from two cells to four cells, are also found to be sensitive to embryo quality. More generally, there has been proposed various approaches for assessing the development potential of an embryo from parameters relating to the embryo's in-vitro development. Consequently, an aim of time-lapse imaging is to establish values for various parameters relating to the timings of various embryo development events and/or other characteristics relating to the development of the embryo, for example in terms of cell-uniformity (evenness) at different stages, the appearance of pro-nuclei (PN), and the presence of multi-nucleation (MN). Establishing values and characteristics relating to embryo development from a series of time-lapse images is sometimes called annotation.
While various timings and characteristics associated with embryo development have been found to help provide quality indicators for development of an embryo, the specific values for these which indicate a good quality embryo can be different for different embryos according to the conditions under which the embryo is incubated and the manner in which the various events are allocated. For example, one clinic might incubate embryos with a certain percentage oxygen atmosphere and temperature while another clinic might incubate embryos with a different percentage oxygen atmosphere and temperature. This can mean the optimum timing for a given morphological event in the development of an embryo may be different for the different clinics/incubator conditions.
FIG. 1 is a graph representing this principle (this graph is highly schematic and is not based on real data). Thus, FIG. 1 shows an example of how implantation likelihood, Imp %, might vary as a function of the timing of an arbitrary developmental event X (e.g. duration of a particular cell cycle or time of a particular cleavage). The solid curve represents the variation in implantation likelihood as a function of the observed timing for X for embryos developed according to a first set of conditions while the dashed curve represents the variation for embryos developed according to a second set of conditions. For example, the solid curve may represent embryos incubated in a relatively low oxygen atmosphere while the dashed curve may represent embryos incubated in a relatively high oxygen atmosphere. As another example, the solid curve might represent embryos that have been fertilised through intracytoplasmic sperm injection (ICSI) while the dashed curve might represent embryos that have been fertilised through in-vitro fertilisation (IVF). As yet another example, the two curves might represent embryos developed at different clinics. The two curves in FIG. 1 are systematically offset from one another because embryos incubated under different conditions will generally develop at different rates in at least some respects.
Accordingly, while FIG. 1 shows the time associated with the developmental event X can be used to identify embryos having relatively high implantation likelihood for embryos developed under both sets of conditions, the actual values of X associated with high implantation likelihood are different for the two groups. For example, for embryos incubated under the first set of conditions (solid line) an optimum range for the timing of X might be considered to be from h1 to h2, while an optimum range for embryos incubated under the second set of conditions (dashed line) might be considered to be from h3 to h4. What this means in practice is that different models for assessing the development potential of embryos will be needed for the different populations.
However, it would be preferable if a single model could be established that is applicable for embryos developed under various different conditions, i.e. what might be termed a universally-applicable model (or at least a model applicable to embryos developed under a range of different conditions). Not only would a universally-applicable model simplify the process of selecting a model to use for different embryo development conditions, in some cases there may not be sufficient KID data available for a given set of development conditions to allow a model for those specific conditions to be reliably established, for example in the case of a “new” clinic. One simple solution for providing a single model for the schematic situation represented in FIG. 1 would be to assume an optimum range for the timing of X of between h1 and h4 for all embryos. However, this would result in embryos from each population being wrongly classified as having high implantation likelihood, which of course is not a satisfactory solution.
Accordingly, there is a desire to develop models for assessing the development potential (viability/quality) of embryos, such as an in-vitro incubating human embryos, which are applicable for embryos developed under a range of different conditions.